Serotonin, also referred to as 5-hydroxytryptamine (5-HT), is a neurotransmitter with mixed and complex pharmacological characteristics. 5-HT acts via a number of discrete 5-HT receptors. Currently, fourteen subtypes of serotonin receptor are recognised and delineated into seven families, 5-HT1 to 5-HT7. Within the 5-HT2 family, 5-HT2A, 5-HT2B and 5-HT2C subtypes are known to exist. The nomenclature and classification of 5-HT receptors has been reviewed by Martin and Humphrey, Neuropharm., 33, 261-273 (1994) and Hoyer, et al., Pharm. Rev., 46, 157-203 (1994).
There is evidence to suggest a role for 5-HT2B receptors in a number of medical disorders, and therefore 5-HT2B receptor antagonists are likely to have a beneficial effect on patients suffering these disorders. They include, but are not limited to: disorders of the GI tract, and especially disorders involving altered motility, and particularly irritable bowel syndrome (WO 01/08668); disorders of gastric motility, dyspepsia, GERD, tachygastria; migraine/neurogenic pain (WO 97/44326); pain (U.S. Pat. No. 5,958,934); anxiety (WO 97/44326); depression (WO 97/44326); benign prostatic hyperplasia (U.S. Pat. No. 5,952,331); sleep disorder (WO 97/44326); panic disorder, obsessive compulsive disorder, alcoholism, hypertension, anorexia nervosa, and priapism (WO 97/44326); asthma and obstructive airway disease (U.S. Pat. No. 5,952,331); incontinence and bladder dysfunction (WO 96/24351); disorders of the uterus, such as dysmenorrhoea, pre-term labour, post-partum remodelling, endometriosis and fibrosis; pulmonary hypertension (Launay, J. M., et al., Nature Medicine, 8(10), 1129-1135 (2002)).
WO 97/44326 describes aryl pyrimidine derivatives and their use as selective 5-HT2B antagonists. However, although this application discloses a number of compounds, it is desirable to find further classes of compounds to act as 5-HT2B antagonists, which are preferably selective against 5-HT2A and 5-HT2C receptors.